Serum protein binding of phenylbutazone has been measured in the rat, guinea pig, cat, rabbit and dog, and the influence on it of renal failure induced by uranyl nitrate injection has been studied. In all speciies a clearcut decrease in binding was observed after the occurrence of renal failure; the time course of the fall in binding correlated well with development of renal failure. In further experiments, serum protein binding of two acidic drugs (phenylbutazone, warfarin), two basic drugs (papaverine, quinidine) and one neutral drug (digitoxin) was studied in rabbits with experimental renal failure, and the results compared with those obtained in patients with acute renal failure. In the rabbits, a decrease in the binding of phenylbutazone, warfarin, papaverine and quinidine was found, whereas protein binding of digitoxin was unchanged. In man, there was a definite fall in protein binding of phenylbutazone and digitoxin, a small decrease for warfarin and papaverine, and a slight increase for quinidine.

1. A gas chromatographic method is described for the quantitative determination of the metabolites of papaverine in urine. 2. The urinary excretion of papaverine metabolites was studied in man. About 50% of the metabolites of papaverine are excreted in the urine within 48 h. 6-Desmethylpapaverine is the major metabolite in the urine. The metabolites are excreted almost completely in conjugated form.

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In vitro binding of phenylbutazone and phenytoin was studied in serum, in tissue homogenates, in tissue slices and in blood cells of rabbits with acute renal failure induced by uranyl nitrate. For phenylbutazone serum binding was decreased in uraemic rabbits, while the binding in homogenates of kidneys and liver was increased. For phenytoin binding in serum and in homogenates and slices of kidneys was decreased in uraemic rabbits. Binding of phenylbutazone and phenytoin to blood cells was not significantly changed in uraemic rabbits. The changes in tissue binding found are small and are only significant for liver and kidney which represent a small fraction of total body mass. Although the methodology for measurement of tissue binding is not entirely satisfactory, we think we can conclude that these changes probably contribute only to a minor degree to the increase of the volume of distribution found for these drugs in renal failure as already suggested by our in vivo data in the preceding paper.

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